Episodic memory declines substantially and, relative to most other forms of memory, disproportionately, with age, while a considerably more severe impairment of episodic memory is a prominent feature of several age-related neurodegenerative disorders. An understanding of the cognitive and neural bases of age-related episodic decline in healthy subjects is important because even the relatively modest impairment typical of healthy individuals entering their 70's is sufficient to have a detrimental impact on cognitive function. Thus, the development of interventions that ameliorate age-related memory decline would be of considerable value and would be much facilitated by increased understanding of its causes. Equally important, a full understanding of the more severe memory impairments characteristic of pathological conditions such as Alzheimer's Disease will be difficult to achieve without knowledge of how memory and its neural substrates change in the course of healthy aging. The overarching aim of the present research program is to elucidate the functional significance of age- related differences in the neural correlates of cognitive processes supporting episodic memory, determining which of these differences reflect processes that contribute to age-related decline in memory function, and which reflect compensatory mechanisms that ameliorate such decline. The focus of the program is on the neural correlates of episodic encoding and retrieval as indexed by fMRI 'subsequent memory'and 'retrieval success'effects. The program takes as its starting point findings indicating that, relative to individuals in their 20's, people in the 60's and 70's demonstrate characteristic differences in the magnitude and cortical distribution of subsequent memory and retrieval success effects. One of these differences takes the form of 'right frontal over-recruitment'- larger subsequent memory effects in the right prefrontal cortex in older relative to younger individuals. Recent findings indicate that right frontal over-recruitment of subsequent memory effects is associated with relatively poor levels of memory performance. Five experiments will be conducted that, together, will rigorously characterize the relationship between neural correlates of episodic encoding and retrieval and age, memory performance, and a variety of structural brain measures including white matter integrity. The studies include a large-scale investigation of encoding- and retrieval-related neural activity in young, middle-aged and older individuals, a longitudinal study permitting investigation of the relationship between encoding and retrieval effects and age-related memory decline, a study to investigate how subsequent memory effects vary with the difficulty of the study task in older people, and an experiment aimed at testing the hypothesis that the neural activity elicited during successful episodic retrieval carries less well- differentiated information in older than in young individuals. PUBLIC HEALTH RELEVANCE: Decline in episodic memory - memory for unique events - is typical of healthy aging and, in a much more exaggerated fashion, of age-related neurodegenerative disorders such as Alzheimer's Disease. The proposed research will contribute to the understanding of the changes in neural activity that accompany age-related decline in episodic memory, and to differences in neural function that may ameliorate or exacerbate such decline.